The use of small molecules to manipulate metabolic function in vivo has emerged as an important new approach to therapy for a wide range of disease pathologies. The amino acid starvation response (AAR) is a signaling pathway that controls a variety metabolic and cytoprotective functions in response to the restriction of amino acid availability. In our preliminary experiments we have found that halofuginone, a small molecule with efficacy in a variety of animal disease models involving fibrosis and angiogenesis, is a potent and specific activator of the AAR. We have also found that halofuginone activates the AAR through a novel mechanism, and acts independently of the best characterized mediator of AAR signaling. Through this novel signaling mechanism, HF regulates a variety of previously described cell behaviors associated with disease pathology or pathogenesis. We have also identified a novel, specific effect of HF on the differentiation in vitro and in vivo pro-inflammatory T-cells. HF alters T-cell populations in vivo in a way predicted by its effects in vitro. HF reduces inflammatory pathology in a mouse model of autoimmunity, indicating that HF has strong potential as a new class of therapeutic for autoimmune and chronic inflammatory disease. These observations open an exciting new set of opportunities for understanding how HF, and other small molecules with similar molecular targets, may have new and unexpected uses for the treatment of pathology associated with chronic inflammatory disease. PUBLIC HEALTH RELEVANCE: We have identified a small molecule that in animal models is effective for the treatment of pathological tissue changes associated with a wide range of diseases, including multiple sclerosis, scleroderma, muscular dystrophy, and diabetic nephropathy. We plan to characterize the mechanism of action of this molecule as a new class of disease therapeutic.